Compositions and Methods for Discovery of Causative Mutations in Genetic Disorders

1. A method of hybridizing a nucleic acid probe or synthesizing a nucleic acid product comprising: (a) hybridizing a nucleic acid probe to a polynucleic acid from at least one subject affected by a disease and at least 100 subjects unaffected by the disease by nucleic acid hybridization or microarray analysis, or synthesizing a nucleic acid product from a polynucleic acid from at least one subject affected by a disease and at least 100 subjects unaffected by the disease by PCR or sequencing, wherein the at least one subject affected by the disease has a phenotype associated with the disease, and the at least 100 subjects unaffected by the disease do not have the phenotype associated with the disease; (b) detecting at least one copy number variation from the polynucleic acid by the nucleic acid hybridization, microarray analysis, PCR or sequencing from the at least one subject affected by the disease, wherein the number of the at least one copy number variation in the at least 100 subjects unaffected by the disease is none or is a number that is a statistically significant amount less than the number of the at least one copy number variation detected in the at least one subject affected by the disease; and (c) sequencing one or more genomic regions encompassing the at least one copy number variation detected in step (b) in one or more subjects affected by the disease and one or more subjects unaffected by the disease, wherein the sequencing detects a first set of genetic variants from the one or more subjects affected by the disease and a second set of genetic variants from the one or more subjects unaffected by the disease, wherein at least one genetic variant of the first set of genetic variants is not present in the second set of genetic variants, or the number of at least one genetic variant of the first set of genetic variants in the second set of genetic variants is a number that is a statistically significant amount less than the number of the at least one genetic variant present in the first set of genetic variants.

2. The method of claim 1 , wherein the whole genome or exome of the at least one subject affected by the disease and the at least 100 subjects unaffected by the disease are analyzed.

3. The method of claim 1 , wherein the at least 100 subjects unaffected by the disease comprise at least 1,000 subjects unaffected by the disease.

4. The method of claim 1 , wherein the one or more subjects unaffected by the disease comprise 20 or more subjects unaffected by the disease.

5. The method of claim 1 , wherein the method further comprises detecting by PCR, junction fragment PCR, multiplex ligation-dependent probe amplification (MLPA), Invader assay, or microarray genotyping one or more genetic variants of the first set of genetic variants or one or more genetic variants of the second set of genetic variants in a genome of 100 or more subjects affected by the disease or 100 or more subjects unaffected by the disease.

6. The method of claim 1 , wherein the at least one copy number variation, the first set of genetic variants, or the second set of genetic variants has a functional impact on a gene or an RNA or a protein product encoded by the gene according to an in silico assay, an in vitro assay, a structural biology method, or a RNAi screening assay; wherein the gene or a portion thereof is encompassed by the one or more genomic regions encompassing the at least one copy number variation.

7. The method of claim 6 , wherein the RNA or the protein product encoded by the gene is a known drug target, impacts a known drug target's mechanism of action, is a binding partner of a known drug target, or is linked to a known drug target via pathway analysis.

8. The method of claim 6 , wherein the RNA or the protein product encoded by the gene is qualified as a drug target via an in silico or an in vitro method for potentially treating a subject affected by the disease and comprising the at least one copy number variation or the at least one genetic variant of the first set of genetic variants.

9. The method of claim 6 , wherein the method further comprises screening a library of small molecule compounds to identify one or more small molecule compounds that impact activity or expression of the RNA or the protein product encoded by the gene.

10. The method of claim 1 , wherein the method further comprises determining whether to enroll or exclude a subject affected by the disease and comprising the at least one copy number variation or the at least one genetic variant of the first set of genetic variants in a therapeutic or diagnostic clinical trial.

11. The method of claim 1 , wherein the method further comprises using tissue from a subject affected by the disease and comprising the at least one copy number variation or the at least one genetic variant of the first set of genetic variants to generate an induced pluripotent stem cell containing the one or more copy number variants or the first set of genetic variants for functional validation of the disease using an in vitro method.

12. The method of claim 1 , wherein the nucleic acid product synthesized from the polynucleic acid is RNA, and the sequencing is transcriptome sequencing.

13. The method of claim 1 , wherein the method further comprises detecting a first epigenetic state by performing an epigenetic analysis of the one or more genomic regions encompassing the at least one copy number variation from the one or more subjects affected by the disease; detecting a second epigenetic state by performing an epigenetic analysis of the one or more genomic regions encompassing the at least one copy number variation from the one or more subjects unaffected by the disease; and detecting by an in silico or an in vitro method a functional impact of the first and second epigenetic states on one or more RNA or protein products resulting from the first or second epigenetic states.

14. The method of claim 1 , wherein the at least one genetic variant encodes one or more RNA variants.

15. The method of claim 1 , wherein the method further comprising administering a drug to a human subject in need thereof comprising the at least one genetic variant of the first set of genetic variants, wherein the at least one genetic variant of the first set of genetic variants occurs within a gene or impacts expression of a gene.

16. The method of claim 1 , wherein the method further comprises detecting a subset of the at least one copy number variation or a subset of the at least one genetic variant of the first set of genetic variants of a genome in a subject affected by the disease.

17. The method of claim 1 , wherein the method further comprising identifying a therapeutic agent that treats the disease.

18. The method of claim 1 , wherein sequencing the one or more genomic regions encompassing the at least one copy number variation comprises sequencing a region upstream or downstream of the at least one copy number variation.